Process for preparing pyridinemethanol compounds

ABSTRACT

A pyridinemethanol compound is an important intermediate for a mirtazapine which is useful as an antidepressant. The pyridinemethanol compound is obtained by reducing potassium pyridinecarboxylate represented by the formula (I):  
                 
 
     with a metal hydride.

[0001] This application is a continuation-in-part application ofPCT/JP00/05384, the entire contents of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a pyridinemethanol compound.More specifically, the present invention relates to a process capable ofsimply and industrially preparing a pyridinemethanol compound, which isan important intermediate for mirtazapine which is useful as anantidepressant, and a process for preparing mirtazapine using thepyridinemethanol compound.

[0004] 2. Discussion of the Related Art

[0005] Conventionally, as a process for preparing a pyridinemethanolcompound represented by the formula (II):

[0006] there has been proposed a process comprising reducing apyridinecarboxylic acid represented by the formula (IV):

[0007] using lithium aluminum hydride (U.S. Pat. No. 4,062,848).

[0008] However, there are some defects in this process that the processis not economical because it is required to use an expensive reagentlithium aluminum hydride in a large amount as much as 8 times equivalentbased on pyridinecarboxylic acid.

[0009] Also, in this process, pyridinecarboxylic acid is obtained bydissolving a pyridinecarbonitrile compound in ethanol, hydrolyzing thepyridinecarbonitrile compound with potassium hydroxide under reflux for24 hours, and thereafter adding an acid thereto to liberatepyridinecarboxylic acid.

[0010] However, there are some defects in this process that itsproduction efficiency is poor because the hydrolysis requires a longperiod of time and there is a necessity to liberate the resultingpyridinecarboxylic acid.

[0011] In addition, conventionally, as a process for preparingmirtazapine, there has been known a process as disclosed in U.S. Pat.No. 4,062,848.

[0012] However, there are some defects in the process that stirring isdifficult because concentrated sulfuric acid is added in a thin streamto the pyridinemethanol compound, so that the reaction control would bedifficult, and that a large amount of an aqueous ammonia is required inorder to make the reaction mixture alkaline with the aqueous ammonia. Inaddition, there are some defects in the process that even the impuritiesare extracted because the reaction product is extracted with chloroform,and that mirtazapine having a high purity cannot be obtained becausecrystallization is inhibited during the crystallization from an ether.

[0013] The present invention has been accomplished in view of the priorart described above. An object of the present invention is to provide aprocess capable of economically and efficiently preparing apyridinemethanol compound.

[0014] Another object of the present invention is to provide a processcapable of efficiently preparing mirtazapine from the above-mentionedpyridinemethanol compound on an industrial scale, to give mirtazapinehaving a high purity.

[0015] These and other objects of the present invention will be apparentfrom the following description.

SUMMARY OF THE INVENTION

[0016] According to the present invention; there are provided:

[0017] (1) a process for preparing a pyridinemethanol compoundrepresented by the formula (II):

[0018] comprising reducing potassium pyridinecarboxylate represented bythe formula (I):

[0019] with a metal hydride; and

[0020] (2) a process for preparing mirtazapine comprising adding apyridinemethanol compound represented by the formula (II):

[0021] to sulfuric acid.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 is a microphotograph of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3 -methanol obtained in Example 4.

[0023]FIG. 2 is a microphotograph of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol obtained in Comparative Example 1.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The potassium pyridinecarboxylate represented by the formula (I):

[0025] can be easily prepared by using a pyridinecarbonitrile compoundrepresented by the formula (III):

[0026] or a salt thereof as a starting material, and reacting thepyridinecarbonitrile compound or a salt thereof with potassium hydroxidein butanol.

[0027] As described above, one of the great features of the presentinvention resides in that the pyridinecarbonitrile compound or a saltthereof is reacted with potassium hydroxide in butanol.

[0028] Conventionally, there is exhibited an especially remarkablyexcellent effect that the reaction time can be surprisingly shortenedfor about not less than 15 hours when both of the compounds are reactedin butanol, while a reaction time of 24 hours or so is required whenethanol is used.

[0029] Furthermore, there is exhibited an especially remarkablyexcellent effect that potassium pyridinecarboxylate formed by thereaction of the pyridinecarbonitrile compound or a salt thereof withpotassium hydroxide can be easily and efficiently extracted from thereaction solution because butanol is used in the present invention.

[0030] The pyridinecarbonitrile compound is concretely2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carbonitrile. As the saltof the pyridinecarbonitrile compound, there can be cited, for instance,oxalates, hydrochlorides, methanesulfonates, and the like of2-(4-methyl-2-phenylpiperazin- 1 -yl) pyridine-3 -carbonitrile.

[0031] As the butanol, there can be cited, for instance, 1-butanol,isobutanol, sec-butanol, and mixed solvents thereof. Among thesebutanols, 1-butanol is preferable. The amount of the butanol is notlimited to specified ones. It is preferable that the amount is usually300 to 800 parts by weight or so, preferably 400 to 600 parts by weightor so based on 100 parts by weight of the pyridinecarbonitrile compoundor a salt thereof, from the viewpoints of shortening the reaction timeand improving the volume efficiency.

[0032] As the form of potassium hydroxide, there can be usually citedflaky, granular, and the like. Among them, flaky is preferable from theviewpoint of solubility.

[0033] It is preferable that the amount of potassium hydroxide isusually 7 to 14 moles, preferably 8 to 12 moles per one mole of thepyridinecarbonitrile compound, from the viewpoint of shortening thereaction time. When the salt of the pyridinecarbonitrile compound isused, it is preferable that potassium hydroxide is further added in anamount required for neutralization because potassium hydroxide isconsumed during the neutralization of the salt.

[0034] It is preferable that the reaction temperature of thepyridinecarbonitrile compound or a salt thereof with potassium hydroxideis usually 120° to 145° C., preferably 120° to 140° C., more preferably130° to 140° C., from the viewpoint of shortening the reaction time. Asdescribed above, as to the temperature of the reaction of thepyridinecarbonitirle compound or a salt thereof with potassiumhydroxide, butanol does not boil even at a temperature of not lower thanthe boiling point of the butanol (e.g. boiling point of 1-butanol: about118° C.) under atmospheric pressure, since potassium hydroxide is used.Therefore, the reaction of both compounds can be efficiently carriedout.

[0035] It is preferable that the reaction is carried out, for instance,in an atmosphere of an inert gas such as nitrogen gas or argon gas, fromthe viewpoint of preventing coloration of the resulting potassiumpyridinecarboxylate represented by the formula (I).

[0036] The period of time required for the reaction of thepyridinecarbonitrile compound or a salt thereof with potassium hydroxidecannot be absolutely determined, because it differs depending upon thereaction temperature of both compounds. The period of time is usually 5to 10 hours or so.

[0037] The termination of the reaction can be confirmed by thedisappearance of the starting materials using, for instance,high-performance liquid chromatography (hereinafter referred to as“HPLC”) or the like.

[0038] The thus obtained potassium pyridinecarboxylate represented bythe formula (I) is specifically potassium2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylate.

[0039] Next, potassium hydroxide in the reaction solution can be removedby adding water to the reaction solution, and allowing the reactionsolution to separate into an organic layer and an aqueous layer, therebytransferring the potassium hydroxide contained in the reaction solutionto the aqueous layer.

[0040] The amount of water used in the separation is not limited tospecified ones. It is preferable that the amount of water is usually 400to 600 parts by weight or so based on 100 parts by weight of thepyridinecarbonitrile compound or a salt thereof, from the viewpoints ofimproving separability and volume efficiency.

[0041] It is preferable that the temperature during the separation is30° to 60° C., from the viewpoints of preventing precipitation ofalkalis and improving extraction efficiency.

[0042] The potassium pyridinecarboxylate can be collected by furtherextracting the aqueous layer with a butanol after the separation,allowing to separate into a butanol layer and an aqueous layer, andtransferring the potassium pyridinecarboxylate existing in the aqueouslayer to the butanol layer.

[0043] Next, the above-mentioned organic layer and butanol layer can becombined, and the butanol and water can be distilled away from theresulting liquid mixture to concentrate the liquid mixture.

[0044] The butanol and water can be distilled away under reducedpressure. It is preferable that the pressure during the distillation isusually 1 to 20 kPa, from the viewpoint of increasing the rate fordistillation. In addition, it is desired that the temperature during thedistillation of the butanol and water is usually 30 to 80° C.,preferably 40° to 60° C., from the viewpoint of increasing the rate fordistillation.

[0045] The amount of the butanol and water distilled away is not limitedto specified ones. It is preferable that the amount is usually 400 to900 parts by weight, preferably 600 to 900 parts by weight based on 100parts by weight of the pyridinecarbonitrile compound or a salt thereof,from the viewpoint of sufficiently distilling away water.

[0046] Next, in order to further distill away moisture and the butanolremaining in the above-mentioned liquid mixture, it is preferable thatthe liquid mixture is mixed with a hydrocarbon, and the resultingreaction solution is heated to azeotropically distill away the butanoland water.

[0047] As the hydrocarbon, there can be cited, for instance, toluene,xylene, benzene, and the like. Among them, xylene is preferable.

[0048] The amount of the hydrocarbon differs depending upon the amountof the butanol and water contained in the mixed solution. It is desiredthat the amount is usually 100 to 600 parts by weight, preferably 200 to300 parts by weight based on 100 parts by weight of thepyridinecarbonitrile compound or a salt thereof, from the viewpoint ofefficiently azeotropically distilling away.

[0049] It is desired that the temperature during the azeotropicdistillation usually satisfies the internal temperature of 110° to 130°C., preferably 120° to 130° C., from the viewpoint of efficientlyazeotropically distilling away.

[0050] It is preferable that the azeotropic distillation is carried outuntil the water content in the mixed solution attains to not more than1% by weight, preferably not more than 0.5% by weight, when determinedby Karl-Fischer method, from the viewpoint of efficiently progressingthe subsequent reduction reaction step.

[0051] Since the hydrocarbon and the butanol are contained in thesolution after the azeotropic distillation, it is preferable to distillaway these solvents. The above distillation can be carried out byheating the reaction solution. In this case, it is desired that theheating temperature usually satisfies the internal temperature of 130°to 140° C., preferably 135° to 140° C., from the viewpoint ofsufficiently distilling away the hydrocarbon and the butanol.

[0052] It is preferable that the amount of the hydrocarbon distilledaway is usually 65 to 90% by weight or so, preferably 80 to 90% byweight or so of the amount of the hydrocarbon used, from the viewpointof sufficiently distilling away the butanol.

[0053] The resulting potassium pyridinecarboxylate may be isolated. Itis preferable that a one-pot reaction of directly reducing a concentrateis carried out. The pyridinemethanol compound represented by the formula(II):

[0054] can be prepared by reducing potassium pyridinecarboxylate with ametal hydride.

[0055] One of the great features of the present invention resides inthat potassium pyridinecarboxylate is reduced with a metal hydride. Thepotassium pyridinecarboxylate has an excellent characteristic that iteasily dissolves in an ether solvent such as tetrahydrofuran(hereinafter referred to as THF) which is used during the reduction.Therefore, the amount of the metal hydride which is used duringreduction can be decreased, and at the same time the potassiumpyridinecarboxylate can be easily reduced with the metal hydride.

[0056] During the reduction of the potassium pyridinecarboxylate withthe metal hydride, the solution from which the hydrocarbon is distilledaway obtained as mentioned above can be directly used. When the abovesolution is used, the pyridinemethanol compound can be directly andefficiently obtained without the isolation of the potassiumpyridinecarboxylate.

[0057] In addition, in the present invention, there is employed not aconventional process of reducing the pyridinecarboxylic acid withlithium aluminum hydride, but a process of reducing the potassiumpyridinecarboxylate with the metal hydride. In the case where thisprocess is employed, there is taken in an excellent effect that theamount of the metal hydride can be remarkably decreased. As the metalhydride, there can be cited lithium aluminum hydride,bis(2-methoxyethoxy)aluminum sodium hydride, diisobutylaluminum hydride,and the like. Among them, lithium aluminum hydride can be favorablyused.

[0058] During the reduction of the potassium pyridinecarboxylate withthe metal hydride, there can be used a solution or suspension in whichthe metal hydride is previously dissolved or suspended in an organicsolvent. As the organic solvent, there can be cited THF, diethyl ether,and the like. Among them, THF can be favorably used, from the viewpointof easy handling.

[0059] In addition, when using a solution in which the above-mentionedhydrocarbon is distilled away, in order to efficiently reduce thepotassium pyridinecarboxylate contained in the solution, it ispreferable that the solution is previously diluted with theabove-mentioned organic solvent. Among the above-mentioned organicsolvents, THE can be favorably used.

[0060] It is desired that the total used amount of the organic solventsis usually 500 to 1200 parts by weight or so, preferably 700 to 900parts by weight based on 100 parts by weight of the potassiumpyridinecarboxylate, from the viewpoint of accelerating the reductionreaction.

[0061] In addition, it is preferable that the amount of the metalhydride is usually 2.5 to 5 moles, preferably 3 to 4 moles per one moleof the potassium pyridinecarboxylate, from the viewpoint of acceleratingthe reduction reaction.

[0062] It is preferable that the atmosphere during the reduction of thepotassium pyridinecarboxylate is an inert gas atmosphere. As the inertgas, there can be cited, for instance, nitrogen gas, argon gas, and thelike. Among them, nitrogen gas is preferable.

[0063] The reduction of the potassium pyridinecarboxylate can be easilycarried out by, for instance, adding in a thin stream a dilute solutionprepared by diluting with an organic solvent the above-mentionedsolution in which the hydrocarbon is distilled away, to a solution orsuspension prepared by dissolving or suspending a metal hydride in anorganic solvent. During the reduction, it is preferable that each of theliquid temperatures of the solution and suspension, prepared bydissolving or suspending a metal hydride in an organic solvent, and thedilute solution is 10° to 50° C., preferably 15° to 35° C., from theviewpoint of efficiently progressing the reduction reaction.

[0064] The period of time required for the reduction reaction of thepotassium pyridinecarboxylate cannot be absolutely determined becausethe period of time differs depending upon the amount of the potassiumpyridinecarboxylate, the reaction temperature, and the like. The periodof time is usually 1 to 6 hours or so.

[0065] The termination of the reaction can be confined by thedisappearance of the potassium pyridinecarboxylate by, for instance,HPLC, or the like.

[0066] After the termination of the reaction, it is preferable thatwater is added in a thin stream to the reaction solution. It is desiredthat the amount of water is 90 to 110 parts by weight, preferably 95 to100 parts by weight based on 100 parts by weight of the metal hydride.Since the reaction solution generates heat during the addition of water,it is preferable that the addition of water is carried out so that theliquid temperature of the reaction solution can be 0° to 20° C.

[0067] Next, an aqueous alkali is added in a thin stream to the reactionsolution. As the alkali usable for the aqueous alkali, there can becited alkali metal hydroxides such as sodium hydroxide and potassiumhydroxide. Among them, sodium hydroxide is preferable. When the aqueoussodium hydroxide is used as an aqueous alkali, it is preferable that theconcentration of sodium hydroxide is usually 20 to 25% by weight or so.It is desired that the amount of sodium hydroxide is usually 0.1 to 0.25moles, preferably 0.15 to 0.2 moles per one mole of the metal hydride.

[0068] During the addition of the aqueous alkali in a thin stream, it isdesired that the liquid temperature of the reaction solution is 0° to30° C., preferably 0° to 15° C.

[0069] Next, in order to improve the slurry property of this reactionsolution, it is preferable to add water thereto. It is desired that theamount of water is 200 to 500 parts by weight, preferably 250 to 400parts by weight based on 100 parts by weight of the metal hydride. Inaddition, it is desired that the temperature during addition of water ina thin stream is 0° to 30° C., preferably 0° to 20° C.

[0070] In order to improve the filterability of a metal hydroxide formedfrom the metal hydride by hydrolysis, it is desired that the reactionsolution is aged at 15° to 30° C. for 30 minutes to 4 hours, preferablyat 20° to 25° C. for 1 to 2 hours.

[0071] Next, the reaction solution is filtered to collect the metalhydroxide by filtration. It is preferable that the liquid temperature ofthe reaction solution during the filtration is 15° to 25° C.

[0072] Since the desired compound, pyridinemethanol compound representedby the formula (II) remains in the collected metal hydroxide, it ispreferable that the metal hydroxide is washed with a solvent such asTHF. The amount of the solvent is not limited to specified ones. It isdesired that the amount of the solvent is usually 500 to 3000 parts byweight, preferably 1000 to 2000 parts by weight based on 100 parts byweight of the metal hydride.

[0073] Next, THF and water are distilled away from the filtrate solutionunder atmospheric pressure until its internal temperature attains toabout 110° C. It is preferable that its distillation amount is 60 to 90%by weight, preferably 65 to 80% by weight of the amount of the THF usedin dissolving and reducing the potassium pyridinecarboxylate used.

[0074] Next, the pyridinemethanol compound is crystallized. It ispreferable that the crystallization is carried out by adding heptane ina thin stream to a solution after distillation. The amount of heptane isnot limited to specified ones, which may be usually the amount that cansufficiently crystallize the pyridinemethanol compound. It is desiredthat the amount of heptane is usually 50 to 300 parts by weight,preferably 90 to 200 parts by weight based on 100 parts by weight of thepotassium pyridinecarboxylate. It is desired that the temperature duringthe addition of heptane in a thin stream is 40° to 90° C., preferably50° to 70° C. The period of time for the addition in a thin stream maydepend upon the amount of the starting materials. The period of time isusually 1 to 2 hours.

[0075] In addition, during the crystallization, seed crystals may beadded. The seed crystals may be added at the beginning of the additionof heptane in a thin stream or in the course of addition in a thinstream. It is preferable that the seed crystals are added at thebeginning of the addition of heptane in a thin stream. The amount of theseed crystals is not limited to specified ones. It is preferable thatthe amount is usually 0.5 to 5% by weight or so of the potassiumpyridinecarboxylate. The temperature during the addition of the seedcrystals may be 50° to 65° C. or so.

[0076] After the termination of the addition of heptane in a thinstream, it is preferable that aging of the slurry mixture is carried outwith cooling. It is preferable that the aging with cooling is carriedout at 0° to 5° C. for 30 minutes to 2 hours.

[0077] Thereafter, the slurry mixture is filtered, and the residue iswashed. The filtration temperature may be 0° to 5° C. Washing can becarried out by using a mixed solvent prepared by mixing an equal volumeof toluene and heptane, and cooling to 0° to 5° C. The amount of themixed solvent is not limited to specified ones. It is preferable thatthe amount is usually 100 to 150 parts by volume based on 100 parts byweight of the potassium pyridinecarboxylate.

[0078] It is preferable that the pyridinemethanol compound is usuallydried at 50 to 60° C. under reduced pressure of 0.6 to 14 kPa.

[0079] The pyridinemethanol compound has a rod-like crystal form asshown in FIG. 1, and an average particle diameter is 75 to 90 μm.Therefore, the pyridinemethanol compound has a desired crystal form,from the viewpoints of filtration, drying, and the like.

[0080] In addition, in the present invention, mirtazapine can beprepared by using the pyridinemethanol compound. More specifically,mirtazapine can be prepared by adding the pyridinemethanol compound tosulfuric acid.

[0081] It is preferable that the atmosphere during the addition of thepyridinemethanol compound to sulfuric acid is, for instance, anatmosphere of an inert gas such as nitrogen gas or argon gas.

[0082] As sulfuric acid, there can be favorably used a concentratedsulfuric acid of which concentration is 97 to 99%. It is desired thatthe temperature of sulfuric acid during the addition of thepyridinemethanol compound is 0° to 40° C., preferably 50 to 35° C., fromthe viewpoints of suppressing heat generation and suppressing theformation of impurities in a tarred state.

[0083] When the pyridinemethanol compound is added to sulfuric acid, itis preferable that the pyridinemethanol compound is added in dividedportions to sulfuric acid, from the viewpoint of efficiently progressingthe reaction. For instance, it is preferable that the pyridinemethanolcompound is added in 5 to 20 divided portions to sulfuric acid.

[0084] It is desired that the amount of sulfuric acid is usually 300 to400 parts by weight, preferably 350 to 400 parts by weight based on 100parts by weight of the pyridinemethanol compound.

[0085] After the addition of the pyridinemethanol compound to sulfuricacid, it is preferable that the mixture is stirred at a temperature of30 to 40° C. or so for 7 to 10 hours or so, in order to accelerate thereaction.

[0086] Thus, the pyridinemethanol compound is subjected to dehydrationand ring closure, and the end point of the ring closure reaction can beconfirmed by HPLC.

[0087] Next, it is preferable to add water to the resulting reactionsolution by means such as addition of water in a thin stream, in orderto decrease the concentration of sulfuric acid. It is preferable thatthe amount of water is 100 to 200 parts by weight or so based on 100parts by weight of the reaction solution, from the viewpoint ofoperability. In addition, it is preferable that the liquid temperatureof the reaction solution during the addition of water is 0° to 30° C. orso, from the viewpoints of suppressing heat generation and suppressingformation of impurities (tarred product).

[0088] Next, it is preferable that an aqueous alkali is added to thereaction solution for the purpose of neutralization. As the alkali,there can be cited, for instance, sodium hydroxide, potassium hydroxide,sodium carbonate, and the like. Among them, sodium hydroxide ispreferable. It is desired that the concentration of the alkali hydroxidein the aqueous alkali is 20 to 25% by weight, from the viewpoint ofoperability. It is desired that the amount of the aqueous alkalihydroxide is 50 to 250 parts by weight, preferably 80 to 110 parts byweight based on 100 parts by weight of the reaction solution.

[0089] After the addition of the aqueous alkali hydroxide, it is desiredthat the pH of its solution is adjusted to 1 to 3, preferably to 1 to 2,in order not to precipitate crystals. The adjustment of the pH can becarried out by, for instance, adding sodium hydroxide or the like to thesolution.

[0090] After the adjustment of the pH, it is preferable thatdecolorizing carbon is added to its solution for decolorizing thesolution.

[0091] Next, mirtazapine can be extracted by filtering this solution,and adding toluene to the filtrate as occasion demands.

[0092] It is desired that the amount of toluene is 100 to 400 parts byweight, preferably 200 to 300 parts by weight based on 100 parts byweight of the pyridinemethanol compound, from the viewpoint ofincreasing yields. After the addition of toluene, it is preferable thatan alkali is added to the mixture at a temperature of 20° to 50° C. toadjust its pH of 8 to 12 in order to completely end the neutralization.As the alkali, there can be cited, for instance, an aqueous sodiumhydroxide and the like.

[0093] Next, it is preferable that this solution is heated to atemperature of 75° to 80° C. in order to dissolve the crystals, therebyimproving separability.

[0094] When this solution is allowed to stand, the mixture is separatedinto two layers. Among them, heptane is added to the organic layer inorder to crystallize mirtazapine. It is desired that the temperatureduring the addition of heptane is 40° to 70° C., preferably 50° to 60°C., from the viewpoint of improving filterability. It is desired thatthe amount of heptane is 50 to 200 parts by weight, preferably 70 to 100parts by weight based on 100 parts by weight of toluene, from theviewpoint of increasing yields. In addition, during the addition ofheptane, it is preferable that the heptane is added in a thin stream. Itis desired that its addition in a thin stream is carried out over aperiod of 1 to 4 hours, preferably 1 to 2 hours.

[0095] Next, it is preferable that the resulting solution is graduallycooled to a temperature of 0 to 5° C. over a period of 1 to 5 hours,preferably 2 to 3 hours, in order to form a uniform crystal and toincrease yields.

[0096] Thus, the mirtazapine can be crystallized, and the crystals maybe washed with a mixed solvent, prepared by, for instance, mixingtoluene with heptane, and cooling the mixture to 0° to 5° C. In thiscase, the ratio of toluene to heptane may be 70 to 100 parts by weightof heptane or so based on 100 parts by weight of toluene.

[0097] Next, the crystals may be dried under reduced pressure at atemperature of 50° to 60° C. or so as occasion demands.

[0098] Thus, mirtazapine can be obtained.

EXAMPLES

[0099] Next, the present invention will be described more specificallyon the basis of the examples, without intending to limit the presentinvention thereto.

Example 1

[0100] To 162 g of 1-butanol were added 60.93 g of potassium hydroxideand 40 g (0.1086 moles) of2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carbonitrile oxalate, andthe resulting mixture was heated at 125 to 135° C. As a result, it wasconfirmed by HPLC that the raw material2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carbonitrile oxalatedisappeared after about 7 hours passed from the addition.

[0101] Two-hundred grams of water was added to the reaction solutionobtained above, and the mixture was allowed to separate into two layersat 40 to 50° C. The aqueous layer was further extracted with 34 g of1-butanol. The butanol layers were combined together, and its pressurewas reduced to 2.6 to 13 kPa. Thereafter, the mixture was concentratedat 40° to 60° C., to distill off 204 g of the solvent.

[0102] Next, 86 g of xylene was added to the resulting solution, and themixture was subjected to azeotropic dehydration at an internaltemperature of 125° to 135° C. When the water content of the mixture wasreduced to 0.487% by weight (determined by Karl-Fischer method), themixture was concentrated at 135° to 140° C. under atmospheric pressure,to distill off 74 g of xylene and water.

[0103] There could be confined that the resulting compound was potassium2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate from thefinding that the retention time in HPLC and the infrared absorptionspectrum (hereinafter referred as “IR”) of the resulting compound wereidentical to those of separately prepared potassium2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate. NMR and IR ofthe resulting potassium 2-(4-methyl-2-phenylpiperazin-l-yl)pyridine-3-carboxylate are as follows.

[0104]¹H-NMR (CDCl₃, 400 MHz) δ=2.00 (br, 1H), 2.10 (s, 3H), 2.32 (br,1H), 2.53 (br, 1H), 2.85 -2.87 (m, 1H), 3.25 -3.33 (m, 2H), 3.65 (br,1H), 5.65 (br, 1H), 6.39 (br, 1H), 6.78 -7.52 (m, 5H), 8.09 (br, 1H) ppmIR (KBr) v =1571, 1453, 1432, 1397, 1374, 759, 705 cm⁻¹

Reference Example

[0105] Potassium2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylate obtained inExample 1 was formed into a free acid with hydrochloric acid, to give2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylic acid.

[0106] NMR and IR of the resulting 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylic acid are as follows.

[0107]¹H-NMR (CDCl₃, 400 MHz) δ=2.47 (s, 3H), 2.60 -2.66 (m, 2H), 3.1-3.156 (m, 3H), 3.486 -3.49 (m, 1H), 4.81 -4.848 (d, 2H), 7.1 -7.266 (m,6H), 8.318 -8.342 (m, 1H), 8.514 -8.531 (m, 1H) ppm IR (KBr) v =1571,1456, 1429, 1386, 1136, 769 cm⁻¹

Example 2

[0108] Eighty-nine grams of THF was added to the reaction solutionobtained in Example 1, to give a THF solution.

[0109] The THF solution was added in a thin stream to a solutionprepared by dissolving 12.5 g of lithium aluminum hydride in 234 g ofTHF at 20° to 30° C. over 30 minutes, and the mixture was stirred at thesame temperature for 3 hours and 30 minutes.

[0110] The disappearance of potassium2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylate was confirmedby HPLC, and 12.2 g of water was added in a tin stream thereto at 20° to30° C. To the mixture were added 12.2 g of a 20% by weight aqueoussodium hydroxide and subsequently 38 g of water, and the mixture washeated for 1 hour.

[0111] The precipitated crystals were filtered, washed with 45 g of THF,and 375 g of THF was distilled off under atmospheric pressure.

[0112] Forty-two grams of heptane was added in a tin stream to thedistilled residue at 48° to 49° C. over 30 minutes with stirring. Themixture was stirred at 0° to 5° C. for one hour, filtered at the sametemperature, washed with a mixed solution of 43 g of toluene and 34 g ofheptane, and dried, to give a compound as crystals (yield: 70.78%).There could be confirmed that the resulting compound was2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol (21.78 g) fromthe finding that the above compound had the following physicalproperties:

[0113] Melting point: 124° to 126° C.

[0114]¹H-NMR (δ:ppm): 8.16 (d, 1H, 2-H: pyridine), 7.36 (d, 1H, 4-H:pyridine), 7.29 (d, 2H, 2-H: phenyl), 7.13 (t, 2H, 3-H: phenyl), 7.07(d, 1H, 4-H: phenyl), 6.88 (dd, 1H, 3-H: pyridine), 5.3 (br, 1H, OH),4.86, 4.60 (d, 2H, CH₂ —-OH), 4.70 (dd, 1H, 2-H: piperazine), 3.18 (m,2H, piperazine), 2.96 (m, 2H, piperazine), 2.46 (m, 1H, piperazine),2.34 (m, 1H, piperazine), 2.37 (s, 1H, N-CH₃)

Example 3

[0115] To 822 kg of 1-butanol was added 309.5 kg of potassium hydroxideflake to dissolve, and 202.9 kg of2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carbonitrile oxalate wasadded thereto at 30° to 50° C. in divided portions. The mixture washeated to 130° to 140° C., and stirred at the same temperature for 9hours. The end point of the reaction was confirmed by HPLC, andthereafter the mixture was cooled to about 50° C., and 1014 kg of waterwas introduced thereinto. The mixture was stirred at 42° to 45° C., andthe mixture was allowed to stand to separate into two layers.

[0116] To the aqueous layer was added 823.5 kg of 1-butanol at 40 to 47°C. with stirring, and the mixture was allowed to stand to separate intotwo layers. The organic layers were combined, and concentrated underreduced pressure until not less than 95% of 1-butanol used was distilledoff. Thereafter, 436.9 kg of xylene was added to the concentrate, andthe mixture was subjected to azeotropic dehydration at an internaltemperature of 120° to 122° C. until its water content attained to notmore than 1%. Further, the mixture was heated at atmospheric pressure todistill off 328 kg of a distillation fraction containing xylene. Theretowas added 430.6 kg of THF, to give a THF solution of potassium2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylate. Its watercontent was 179.5 ppm.

Example 4

[0117] To 889.15 kg of THF was added 65.6 kg of lithium aluminum hydrideunder nitrogen atmosphere, and the resulting solution was stirred for 2hours. To this solution was added in a thin stream the THF solution ofpotassium 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylateobtained in Example 3 at 20° to 25° C. A vessel in which the potassiumsalt solution had been placed was washed with 21.4 kg of THF, and theresulting washing liquid was added to the reaction solution. The mixturewas stirred at 23° to 25° C. for 3 hours. Thereafter, 62.6 kg of waterwas added in a thin stream thereto at 1° to 15° C., and 50.2 kg of a 25%by weight aqueous sodium hydroxide was added in a thin stream to themixture at 4° to 15° C., and further 188.3 kg of water was added in athin stream to the mixture at 10° to 20° C. The mixture was stirred at20° to 25° C. For 70 minutes, and thereafter filtered, and aluminumhydroxide formed by hydrolysis of lithium aluminum hydride was washedwith 903.5 kg of THF.

[0118] Under atmospheric pressure, 2535 L of THF was distilled off at aninternal temperature up to 110° C., and 50 g of seed crystals of2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol were added tothe concentrate, and the mixture was stirred for 30 minutes. Thereto wasadded in a thin stream 215 kg of heptane at 50° to 65° C., and themixture was cooled to 0° to 5° C., and aged for 1 hour. The mixture wasfiltered, and the crystals were washed with a solution prepared bymixing 110.5 kg of toluene with 87.1 kg of heptane and cooling themixture to 0° to 5° C. The washed crystals were dried at 50° to 60° C.,to give 124 kg of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. Its yield [yield based on2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carbonitrile oxalate] was79.4%, and the HPLC purity was 99.7%.

[0119] The physical properties of the resulting2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol are as follows.

[0120] Melting point: 120.6° to 121.6° C.

[0121] IR(KBr)v=1573, 1429, 1128, 1036, 757.8, 701 cm⁻¹

[0122] In addition, the microphotograph of the resulting2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol is shown in FIG.1.

Comparative Example 1

[0123] In 150 mL of THF was dissolved 10.2 g of2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylic acid undernitrogen atmosphere. To 300 mL of THF was added 10.2 g of lithiumaluminum hydride, and the above THF solution was added in a thin streamto the mixture over 50 minutes under reflux. After refluxing the mixturefor 4 hours, the mixture was cooled to 0° to 5° C., and 40.5 mL of waterwas gradually added in a thin stream thereto. Aluminum hydroxide wasseparated therefrom by filtration, and the filtrate was concentratedwith an evaporator. The residue was allowed to recrystallize from anether, to give 8.6 g of2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. Its yield was98%.

[0124] The microphotograph of the resulting2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-methanol is shown in FIG.2.

Example 5

[0125] To 442.6 kg of 98% concentrated sulfuric acid was added individed portions 123 kg of2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol over 3 hours at5° to 32° C. under nitrogen atmosphere, and the mixture was stirred at30° to 40° C. for 7 hours. The disappearance of the starting materialswas confirmed by HPLC, and the resulting reaction solution was added ina thin stream to 885 kg of water at 0° to 30° C. The vessel in which thereaction solution had been placed was washed with 55 kg of sulfuricacid, and the resulting washing liquid was added to the hydrolyzedsolution.

[0126] To the hydrolyzed solution was added in a thin stream 1285 g of a25% aqueous sodium hydroxide at a temperature of 0° to 30° C. to adjustits pH to 1 to 2. To the resulting solution was added 6 kg ofdecolorizing carbon, and the mixture was stirred and filtered. Thedecolorizing carbon was washed with 118 kg of water. To the filtrate wasadded 159.1 kg of toluene, and the mixture was stirred at 20° to 30° C.For 15 minutes and allowed to stand to separate into two layers.

[0127] To the aqueous layer was added 159.1 kg of toluene, and 450.3 kgof a 25% aqueous sodium hydroxide was added to the mixture at 20° to 50°C. to adjust its pH to 11. The solution was heated to 75° to 80° C., andstirred for 15 minutes. The solution was allowed to stand for 90 minutesto separate into two layers. To the organic layer was added in a thinstream 126 kg of heptane at 50° to 60° C. over 65 minutes. The mixturewas cooled to 0° to 5° C. over 3 hours and 40 minutes, and filtered. Theresulting crystals were washed with a solution prepared by mixing 122.3kg of toluene with 97 kg of heptane and cooling the mixture to 0° to 5°C. The crystals were dried at 50° to 60° C. under reduced pressure, togive 103.2 kg of mirtazapine. Its yield was 86.7%, and the HPLC puritywas 99.8%.

Comparative Example 2

[0128] To 28 g of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanolwas added in a thin stream 100.8 g of 98% concentrated sulfuric acid atroom temperature (25° to 30° C.) under nitrogen atmosphere. During thecourse of reaction, stirring became difficult, and the mixture partiallyheated up to near 50° C. The mixture was stirred at 30° to 40° C. For 2hours. Since 8% of the intermediate still remained according to HPLC,the mixture was stirred for additional 6 hours. To the reaction solutionwas added 240 g of ice. As a result, the mixture heated up violently.Thereto was added 161 g of concentrated aqueous ammonia to make thesolution alkaline (pH 9).

[0129] The solution was extracted with 200 mL of chloroform. The organiclayer was dried over anhydrous magnesium sulfate, and concentrated withan evaporator. An ether was added to an oily residue with stirring tosolidify the oily residue. The mixture was filtered. The residue wasdried, and the solid products were recrystallized from petroleum ether40 -60. However, the resulting solid products were pale yellow crystalshaving poor crystallinity and being in a state where the oil waspartially solidified.

[0130] The crystals were filtered and dried, to give 20.1 g of paleyellow mirtazapine. Its yield was 76.6%, and the HPLC purity was 98.3%.

[0131] According to the process of the present invention, thepyridinemethanol compound represented by the formula (II) can beeconomically and efficiently prepared in a short period of time from thepotassium pyridinecarboxylate represented by the formula (I). Also,according to the process of the present invention, the pyridinemethanolcompound can be efficiently prepared in a short period of time from thepyridinecarbonitrile compound represented by the formula (I) or a saltthereof.

[0132] In addition, the mirtazapine can be favorably prepared form thepyridinemethanol compound.

[0133] Equivalent

[0134] Those skilled in the art will recognize, or be able to ascertainusing simple routine experimentation, many equivalents to the specificembodiments of the invention described in the present specification.Such equivalents are intended to be encompassed in the scope of thepresent invention as recited in the following claims.

What is claimed is:
 1. A process for preparing a pyridinemethanolcompound represented by the formula (II):

comprising reducing potassium pyridinecarboxylate represented by theformula (I):

with a metal hydride.
 2. The process according to claim 1, wherein saidpotassium pyridinecarboxylate represented by the formula (I) is preparedby reacting a pyridinecarbonitrile compound represented by the formula(III):

or a salt thereof with potassium hydroxide in butanol.
 3. A process forpreparing mirtazapine comprising adding a pyridinemethanol compoundrepresented by the formula (II):

to sulfuric acid.
 4. The process according to claim 3, wherein thepyridinemethanol compound represented by the formula (II) is added individed portions to sulfuric acid.
 5. The process according to claim 3or 4, wherein the formed mirtazapine is crystallized with toluene andheptane.